Artificial Sweetener and the Risk of Adverse Pregnancy Outcomes: A Mendelian Randomization Study

Abstract

The relationship between the intake of artificial sweetener (AS) and adverse pregnancy outcomes is under-researched, and existing studies yield inconsistent conclusions. A Mendelian randomization (MR) approach was employed to investigate the causal relationship between the intake of AS and adverse pregnancy outcomes. Instrumental variables related to the exposure phenotype were selected for analysis. The analysis was conducted using genome-wide association study summary data from public datasets. The inverse variance weighted, MR-Egger, weighted median, simple mode, and weighted mode methods were used to evaluate the causal relationship between exposure and outcomes. Sensitivity analysis and multivariable Mendelian randomization enrolling body mass index, type 2 diabetes mellitus, and fasting glucose were employed to further validate the consistency and robustness of the results. In univariable MR, the intake of AS added to tea was associated with an increased risk of ectopic pregnancy [OR = 1.821 (1.118-2.967), p = 0.016]. In multivariable MR adjusting for body mass index and type 2 diabetes mellitus, the intake of AS added to cereal was linked to a reduced risk of ectopic pregnancy [OR = 0.361 (0.145-0.895), p = 0.028] and premature rupture of membranes [OR = 0.116 (0.019-0.704), p = 0.019], while the intake of artificial sweetener added to coffee was associated with an increased risk of placenta previa [OR = 1.617 (1.042-2.510), p = 0.032]. No causal relationship was identified between the intake of artificial sweetener and other adverse pregnancy outcomes. The consumption of artificial sweetener during pregnancy warrants careful consideration.

Keywords: Mendelian randomization; adverse pregnancy outcome; artificial sweetener; ectopic pregnancy; placenta previa; premature rupture of membranes.

Figure 1

The overall flowchart of the two-sample Mendelian randomization study. BMI, body mass index; T2DM, type 2 diabetes mellitus.

Figure 2

Causal relationships between the intake of AS and APOs in UVMR. (A) Results of IVW between the intake of AS added to cereal and APOs. (B) Results of IVW between the intake of AS added to coffee and APOs. (C) Results of IVW between the intake of AS added to tea and APOs. AS, artificial sweetener; APOs, adverse pregnancy outcomes; UVMR, univariable Mendelian randomization; IVW, inverse variance weighted; AP, abruptio placenta (O15_PLAC_PREMAT_SEPAR); EP, ectopic pregnancy (GCST90272883); EV, excessive vomiting in pregnancy (O15_EXCESS_VOMIT_PREG); EV2, excessive vomiting in pregnancy (GCST90044480); GDM, gestational diabetes mellitus (GEST_DIABETES); GDM2, gestational diabetes mellitus (GCST90296696); HB, disorders associated with long gestation and high birth weight (R10_P16_DISORD_RELATED_LONG_GESTATION_HIGH_BIRTHWGHTT); ICP2, intrahepatic cholestasis of pregnancy (O15_ICP_WIDE); ICP2, intrahepatic cholestasis of pregnancy (GCST90095084); LB, disorders related to short gestation and low birth weight (R10_P16_DISORD_RELATED_GESTATION_LOW_BIRTHWGHTT_NECIFIED); MD, medical abortion (O15_ABORT_MEDICAL); PB, preterm birth (O15_PRETERM); PB2, preterm birth (GCST008754); PB3, preterm birth (GCST008753); PB4, preterm birth (GCST90271753); PB5, preterm birth (GCST90271755); PD, placental disorders (O15_PLAC_DISORD); PE, pre-eclampsia (O15_PREECLAMPS); PH, pregnancy hypertension (O15_HYPTENSPREG); POE, pre-eclampsia or eclampsia (O15_PRE_OR_ECLAMPSIA); PP, placenta previa (O15_PLAC_PRAEVIA); PROM, premature rupture of membranes (O15_MEMBR_PREMAT_RUPT); SA, spontaneous abortion (O15_ABORT_SPONTAN); SA2, spontaneous abortion (ukb-d-O03).

Figure 3

Causal relationships between the intake of AS adjusting for confounders and APOs in MVMR. (A) Results of IVW between the intake of AS added to cereal and APOs. (B) Results of IVW between the intake of AS added to coffee and APOs. (C) Results of IVW between the intake of AS added to tea and APOs. AS, artificial sweetener; APOs, adverse pregnancy outcomes; MVMR, multivariable Mendelian randomization; IVW, inverse variance weighted; AP, abruptio placenta (O15_PLAC_PREMAT_SEPAR); EP, ectopic pregnancy (GCST90272883); EV, excessive vomiting in pregnancy (O15_EXCESS_VOMIT_PREG); EV2, excessive vomiting in pregnancy (GCST90044480); GDM, gestational diabetes mellitus (GEST_DIABETES); GDM2, gestational diabetes mellitus (GCST90296696); HB, disorders associated with long gestation and high birth weight (R10_P16_DISORD_RELATED_LONG_GESTATION_HIGH_BIRTHWGHTT); ICP2, intrahepatic cholestasis of pregnancy (O15_ICP_WIDE); ICP2, intrahepatic cholestasis of pregnancy (GCST90095084); LB, disorders related to short gestation and low birth weight (R10_P16_DISORD_RELATED_GESTATION_LOW_BIRTHWGHTT_NECIFIED); MD, medical abortion (O15_ABORT_MEDICAL); PB, preterm birth (O15_PRETERM); PB2, preterm birth (GCST008754); PB3, preterm birth (GCST008753); PB4, preterm birth (GCST90271753); PB5, preterm birth (GCST90271755); PD, placental disorders (O15_PLAC_DISORD); PE, pre-eclampsia (O15_PREECLAMPS); PH, pregnancy hypertension (O15_HYPTENSPREG); POE, pre-eclampsia or eclampsia (O15_PRE_OR_ECLAMPSIA); PP, placenta previa (O15_PLAC_PRAEVIA); PROM, premature rupture of membranes (O15_MEMBR_PREMAT_RUPT); SA, spontaneous abortion (O15_ABORT_SPONTAN); SA2, spontaneous abortion (ukb-d-O03).

Figure 4

Causal relationships between the intake of AS and APOs in UVMR and MVMR. (A) Results of IVW between the intake of AS added to cereal and ectopic pregnancy adjusting for different confounders. (B) Results of IVW between the intake of AS added to cereal and placenta previa adjusting for different confounders. (C) Results of IVW between the intake of AS added to coffee and PROM adjusting for different confounders. AS, artificial sweetener; APOs, adverse pregnancy outcomes; UVMR, univariable Mendelian randomization; MVMR, multivariable Mendelian randomization; IVW, inverse variance weighted; PROM, premature rupture of membranes.